Down's syndrome (D.S.) is the most common of genetic abnormalities, occurring once per 1,000 live births. It results from the presence in the cell of an extra copy of chromosome 21, or a portion of it, the 21q22 band. The assumption is that the additional 21q22 segment codes for normal products and that the abnormalities found in the syndrome are produced by an imbanlance due to changes in gene dosage. The long-term goal of this research is to elucidate, at the molecular level, the mechanisms whereby the third copy of 21q22 produces D.S. In the proposed plan of work, the genes residing at the 21q22 region will be cloned and characterized, their structure and organization will be analyzed and polymorphic markers within them will be identified by detailed mapping. Each cloned gene will serve as a starting point for chromosome walking, in order to isolate the neighboring gene. The expression of each isolated gene will be examined in trisomy 21 cells and in organs of aborted D.S. fetuses, to determine the dosage effect. For identification of the genes responsible for the clincal symptoms of the syndrome, normal cells programmed to express elevated levels of the gene will be examined for consequent metabolic changes. The influence exerted on development and morphogenesis by overexpression of a specific gene will be studied by transferring the gene of interest into mouse embryos to produce transgenic mice overexpressing this gene. The information obtained in this study should permit definition of the biochemical pathways affected in the syndrome and therefore allow the development of therapies to ameliorate or prevent at least some of the symptoms of D.S. and related disorders.